Advances in metal-organic frameworks (MOFs) for nanotheranostics: from targeted drug delivery to multimodal imaging

Abstract

The integration of diagnostic and therapy into a single nanoplatform has been proved to be a revolutionary approach for precision medicine, which allows the simultaneous disease detection, treatment, and therapeutic monitoring. Although great progress has been achieved in nanotheranostics, many traditional nanomaterials still suffer from low drug loading capacity (LC), inefficient targeting, insufficient reactivity to the complex tumor microenvironment (TME), and limited integration of diagnostic and therapeutic functions. These issues have led to increased interest in metal–organic frameworks (MOFs), a flexible family of crystalline porous materials built from metal ions or clusters bridged by organic ligands. The ultra-high surface area, customizable pore architecture, programmable composition, structural diversity, and simple surface functionalization have made MOFs interesting candidates for next-generation nanotheranostic systems. MOFs have emerged as adaptable platforms for the concurrent administration of therapeutic drugs and imaging probes, enabling integrated theranostic applications, as evidenced by recent advancements. Moreover, the integration of stimuli-responsive drug release, TME-activated catalytic therapeutic mechanisms, and multimodal imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT), fluorescence imaging (FL), photoacoustic imaging (PAI), and positron emission tomography (PET) has significantly broadened the scope of MOF-mediated precision diagnosis and therapy. In addition to conventional drug delivery, novel MOF nanoplatforms have been designed to induce ferroptosis, chemodynamic therapy, phototherapy (PT), immunomodulation, and other synergistic therapeutic methods, thus improving therapeutic efficacy with minimized off-target harm. This review highlights the recent advances in MOF nanotheranostics covering design strategies, targeted drug delivery, imaging and multifunctional therapeutic applications. The challenges of biosafety, biodegradation, pharmacokinetics, large-scale manufacturing and clinical translation are critically discussed.

Graphical abstract

Highlights

Metal–organic frameworks (MOFs) serve as versatile platforms in nanotheranostics, seamlessly integrating diagnostic and therapeutic functions.

The intrinsic properties of MOFs—including high surface area, tunable porosity, and surface functionalization—enable precise drug delivery and improved imaging contrast.

Recent advances in MOF-based nanoplatforms exhibit enhanced biocompatibility, targeted delivery, and multimodal imaging capabilities, paving the way for precision medicine in cancer diagnosis and treatment.

Introduction

Nanotheranostics is an emerging interdisciplinary field that integrates diagnostic and therapeutic functions within a single nanoplatform, offering new opportunities for more precise and personalized patient care [1]. Unlike conventional treatment approaches, which often suffer from limited efficacy, nonspecific distribution, and variable patient responses, nanotheranostic systems are designed to simultaneously diagnose disease, deliver therapy, and monitor treatment outcomes. By combining imaging and therapeutic capabilities within a single platform, nanomaterials enable real-time visualization of disease progression, accurate localization of tumors, and assessment of therapeutic responses while concurrently delivering treatment. As a result, theranostic agents have the potential to improve treatment precision, enhance therapeutic efficacy, and support the development of personalized medicine strategies [2]. Although nanotheranostics has shown tremendous potential, several obstacles continue to limit its successful clinical translation. One of the major challenges is achieving the high sensitivity, specificity, and detection accuracy required for reliable early disease diagnosis. In addition, improving the pharmacokinetic and pharmacodynamic behavior of nanotheranostic agents remains essential for maximizing therapeutic performance. To address these issues, considerable efforts have focused on optimizing nanocarrier design through structural modifications [3, 4] and advanced nanoformulation strategies [5], which can enhance biodistribution, prolong circulation time, improve target-site accumulation, and ultimately lead to better therapeutic outcomes [6–8]. In addition to challenges related to efficacy, safety remains a major concern in the clinical development of nanotheranostic systems. Adverse effects, ranging from acute toxicity to long-term immunotoxicity, continue to be among the leading factors limiting clinical success and have driven the search for safer and more effective nanomaterials. In this context, metal–organic frameworks (MOFs) have emerged as a highly promising class of porous hybrid materials formed through the coordination of metal ions or clusters with organic ligands. Their unique physicochemical characteristics—including tunable particle size and morphology, adjustable porosity, exceptionally high surface area, compositional versatility, and ease of functionalization—provide remarkable flexibility for biomedical applications. These advantages have positioned MOFs as attractive platforms for drug delivery, cancer therapy, and other advanced nanomedicine applications [9].

This study summarizes current achievements in MOFs for nanotheranostics, with particular emphasis on their application in drug administration, biomedical imaging, and combination therapy. MOFs are especially suitable for drug delivery due to their high LC% and regulated release, enabling the delivery of a wide variety of therapeutic agents, including small molecules, proteins, and nucleic acids [10]. MOFs have been synthesized for improving different imaging techniques like computed tomography (CT), magnetic resonance imaging (MRI), optical imaging (OI) including fluorescence imaging (FL), positron emission tomography (PET) and photoacoustic imaging (PAI) by incorporating specific metal ions or functional groups that function as contrast agents or carriers of imaging probes [11]. Moreover, MOFs have shown considerable promise in combination therapy by enabling the simultaneous delivery of multiple therapeutic agents and the integration of complementary treatment modalities. For example, MOF-based platforms can combine chemotherapy with photodynamic therapy (PDT) or photothermal therapy (PTT), thereby producing synergistic therapeutic effects, enhancing treatment efficacy, and overcoming some of the limitations associated with single-modality therapies [12]. In this review, recent progress and achievements in the application of MOFs as multifunctional nanotheranostic platforms for effective disease therapy, with special emphasis on cancer, are reviewed. We also cover their use in mono-modal (e.g. MRI, CT, PET and PAI) and multimodal imaging methods. Finally, we discuss the remaining problems and new prospects for MOFs in nanotheranostics, providing insights to guide future scientific advances in this vibrant field.

MOFs preparation and fabrication

A variety of synthesis approaches have been developed to fabricate MOFs for drug-delivery applications, including one-pot synthesis, room-temperature methods, solvothermal and hydrothermal techniques, as well as electrochemical, microwave-assisted (MW), sonochemical, and mechanochemical strategies. These methods provide flexibility in controlling the structural and physicochemical properties of MOFs, allowing their design to be tailored for specific biomedical applications.

One-pot synthesis

In the one-pot synthesis approach, the reaction precursors are dissolved in a suitable solvent and allowed to react under continuous stirring within a single reaction vessel. This method is widely used because of its operational simplicity, cost-effectiveness, minimal equipment requirements, and ability to produce relatively high yields. Additionally, the continuous addition of reagents can help maintain stable reaction conditions and improve process safety. However, a notable limitation of this technique is that the resulting MOFs may exhibit lower purity compared with those synthesized using more controlled preparation methods [13]. For example, one-pot biomimetic mineralization is driven by coordination-mediated self-assembly, where simultaneous Zn²⁺/Cu²⁺–2-methylimidazole (2-MIM) coordination promotes rapid nucleation and crystal growth, while excess ligand suppresses metal hydroxide precipitation and enables homogeneous crystallization. Concurrent biomimetic encapsulation of glucose oxidase (GOx) during framework formation preserves enzymatic activity, and in situ Cu²⁺ substitution for Zn²⁺ yields uniform metal incorporation without compromising the ZIF-8 structure. This integrated coordination process enables the rational synthesis of structurally stable, compositionally homogeneous, and multifunctional MOFs for theranostic applications [14].

Room temperature synthesis

This approach represents a distinct class of solvothermal synthesis in which MOFs are formed and crystallized at room temperature without external heating. Crystallization occurs under mild conditions, typically facilitated by bases such as triethylamine that promote ligand deprotonation and MOF precipitation. The method is favored for its simplicity, ease of operation, and good yields without additional energy input; however, it is time-consuming, often requiring hours to days, and may involve hazardous reagents such as DMF or hydrofluoric acid [15]. For example, the template-free, room-temperature synthesis of Cu₂BTEC MOF nanowires is driven by coordination-mediated self-assembly, in which ethanol acts as both a solvent and a structure-directing agent through hydrogen bonding with H₄BTEC linkers. Upon Cu²⁺ addition, ligand deprotonation enables rapid Cu²⁺–carboxylate coordination, replacing hydrogen-bonded assemblies with MOF that promote controlled nucleation and anisotropic crystal growth. Ethanol further facilitates crystallization by acting as a weak Lewis base, yielding highly crystalline nanowires through a solvent-mediated, coordination-driven self-assembly mechanism [16].

Solvothermal/hydrothermal synthesis

The solvothermal method remains the most widely used technique for MOF synthesis. In this approach, metal salts and organic ligands react in a solvent within a sealed vessel, where elevated temperature and pressure promote self-assembly and crystal growth. When water is used as the solvent, the process is referred to as hydrothermal synthesis [17]. The choice of solvent, such as acetone, ethanol, or dimethylformamide, affects both reagent solubility and reaction temperature. Conventional electric heating is typically applied over extended durations, although alternative energy sources may also be employed [18]. For example, solvothermal synthesis relies on thermodynamically controlled MOF under elevated temperature and autogenous pressure, promoting regulated nucleation and crystal growth. In MOF-5, Zn²⁺ ions coordinate with terephthalate (BDC²⁻) linkers to form Zn₄O secondary building units that self-assemble into a highly crystalline porous framework, while DMF enhances precursor solubility, maintains coordination equilibrium, and directs crystal growth, yielding MOFs with uniform morphology, high crystallinity, and tunable porosity [19].

Electrochemical synthesis

Electrochemical synthesis offers a rapid and mild route for MOF preparation while preventing the introduction of unwanted anions such as halides, perchlorates, or nitrates. In this method, metal ions are generated in situ through anodic dissolution and introduced into a solution containing organic ligands and an electrolyte, eliminating the need for metal salts. Protic solvents are commonly used to avoid metal deposition at the cathode, although hydrogen gas is generated. This technique enables fast MOF synthesis at low temperatures without anionic residues, while reaction time and solvent composition strongly influence MOF structure and morphology [15]. For example, electrochemical MOF synthesis is driven by in situ anodic generation of Cu²⁺ ions, which coordinate with multicarboxylate linkers to promote rapid heterogeneous nucleation and controlled crystal growth. Pulsed-current regulation enhances crystallinity and morphology, while linker geometry governs framework topology, with H₃BTC yielding non-interpenetrated structures and H₃TATB favoring interpenetration. Surface-confined growth suppresses framework interpenetration, enabling precise control over porosity, morphology, and crystallinity through coordinated metal-ion generation, nucleation kinetics, and linker-directed self-assembly [20].

Sonochemical synthesis

Sonochemical, or ultrasound (US)-assisted, synthesis (20 kHz–10 MHz) offers a rapid and environmentally friendly method for MOF preparation. This technique accelerates homogeneous nucleation, produces smaller particles, and significantly reduces crystallization time compared with solvothermal methods. High-energy US induces acoustic cavitation—the formation, growth, and collapse of bubbles under alternating pressure—generating localized temperatures of 5000–25,000 K and high pressures with rapid heating and cooling rates [15]. For example, sonochemical synthesis is driven by US-induced acoustic cavitation, which accelerates MOF, nucleation, and crystal growth through localized high-temperature and high-pressure microenvironments. In the synthesis of Zr-fumarate MOF (MOF-801), Zr⁴⁺ ions derived from ZrOCl₂ coordinate with fumarate ligands to form robust Zr₆-oxo secondary building units (SBUs), which subsequently self-assemble into a three-dimensional microporous framework through Zr–carboxylate coordination bonds. Formic acid serves as a coordination modulator to precisely control nucleation kinetics, while DMF facilitates precursor solubilization and coordination equilibrium, collectively promoting the rapid assembly of highly crystalline, thermally stable MOFs with well-defined microporosity and morphology [21].

Microwave-assisted (MW) synthesis

MW irradiation is a promising alternative to conventional MOF synthesis methods and has been widely adopted due to its significant advantages. Rapid and energy-efficient heating, along with higher yields and purity, makes this technique more time- and energy-efficient than traditional approaches. MW heating relies on the direct interaction of electromagnetic radiation with the reaction medium, increasing molecular collisions and kinetic energy, thereby uniformly elevating the system temperature. This enhanced heating efficiency promotes high nucleation rates and rapid crystallization, enabling MOF formation within minutes rather than the prolonged annealing times required for conventional solvothermal methods [15]. For example, MW synthesis is driven by volumetric dielectric heating, which accelerates MOF, homogeneous nucleation, and crystal growth. In MIL-100(Fe), Fe³⁺ ions coordinate with BTC³⁻ linkers to form Fe–carboxylate secondary building units, while HNO₃ regulates nucleation kinetics and the H₂O/DMF solvent system maintains precursor solubility and coordination equilibrium. Coupled with continuous-flow processing, this approach enables the rapid formation of highly crystalline, porous MOFs with uniform morphology and high space–time yield [22].

Mechanochemical synthesis

Mechanochemical synthesis is a solvent-free approach in which mechanical energy, such as ball milling or grinding, induces reactions between solid precursors. Metal salts and organic ligands are ground together, followed by mild heating to remove volatile byproducts such as water. This green, scalable method accommodates insoluble precursors, operates at room temperature, and avoids organic solvents by promoting bond cleavage through mechanical force [18]. Mechanochemical (solvent-free) synthesis is driven by mechanically activated MOF, where grinding initiates heterogeneous nucleation and crystal growth through direct coordination between Cu²⁺ ions and isonicotinate ligands. The resulting Cu(II) nodes self-assemble into a highly crystalline three-dimensional microporous framework, while thermal activation removes trapped by-products to generate permanent porosity. Crystal morphology is further governed by grinding duration, making mechanochemical synthesis an efficient, environmentally sustainable approach for producing crystalline MOFs without solvents, post-synthetic encapsulation, or metal substitution [23].

Structural and functional properties of MOFs in nanotheranostics

The biomedical performance of MOFs is largely determined by the rational selection of their fundamental building blocks, namely metal ions and organic ligands. For nanotheranostic applications, metals such as Zr, Cu, Fe, Mg, Zn, and Mn are frequently employed owing to their favorable biocompatibility, stability, and functional versatility, while organic ligands including 2-methylimidazole, fumaric acid, gallic acid, terephthalic acid, and trimesic acid contribute to framework architecture and physicochemical properties [24]. The wide range of available metal–ligand combinations enables the design of MOFs with tunable structures, controlled degradation profiles, and optimized biological performance. Since biocompatibility and toxicity are strongly influenced by chemical composition, factors such as degradation behavior, biodistribution, tissue accumulation, excretion pathways, and dosage must be carefully considered. In this regard, metal ions such as Ca, Mg, Zn, Fe, Ti, and Zr are generally regarded as suitable candidates for biomedical applications because of their relatively low toxicity and favorable safety profiles [25, 26].

Beyond providing structural support, metal nodes play critical roles in both therapeutic and diagnostic functions. Metals such as Fe, Zn, and Cu can act as catalytic centers that mimic natural enzymes, enabling MOFs to function as nanozymes for reactive oxygen species (ROS) regulation. Certain metal-containing MOFs can also participate in catalytic therapeutic processes and redox modulation, while porphyrin-containing systems [27] further contribute intrinsic therapeutic and antioxidant activities. In addition to therapy, metal nodes provide important imaging functionalities. For example, Fe-, Mn-, and Gd-based MOFs have been extensively investigated as MRI contrast agents, whereas high-atomic-number metals such as Hf and Zr exhibit strong X-ray attenuation properties suitable for CT imaging and radiotherapeutic applications [28, 29]. Furthermore, incorporation of radionuclides such as ⁸⁹Zr and ⁶⁴Cu enables PET imaging, facilitating non-invasive visualization of biological processes and image-guided therapeutic interventions [30].

Equally important are the organic ligands, which not only determine framework topology and stability but also influence drug-loading behavior and biological performance. A variety of exogenous ligands have been employed to construct bio-relevant MOFs, including magnesium coordination polymers [31], iron (III) polycarboxylates [32], and zinc-based frameworks [33]. The resulting porous architectures provide exceptionally high surface areas, typically ranging from 1,000 to 10,000 m² g⁻¹, together with precisely tunable pore structures that facilitate the encapsulation and controlled release of diverse therapeutic cargos [34, 35]. These characteristics contribute to improved drug solubility, stability, bioavailability, and targeting efficiency [18, 34]. Moreover, the remarkable structural diversity arising from different metal–ligand combinations allows MOFs to be tailored for specific biomedical applications. Many MOFs also exhibit excellent thermal and mechanical stability, enabling post-synthetic modification (PSMs) and functionalization strategies that further expand their utility as advanced nanotheranostic platforms [35].

Post-synthetic modification (PSM) of MOFs

Surface modification is a widely used approach for improving the stability, biodistribution, and circulation behavior of nanoscale MOFs (NMOFs), ultimately enhancing their ability to achieve targeted delivery. Among the available strategies, PSM has emerged as a powerful tool for introducing a broad range of functional groups into preformed MOF structures. PSM can be accomplished through various approaches, including metal exchange, ligand exchange, guest-molecule replacement, and the metalation of open coordination sites, either individually or in combination [36]. A key requirement of these processes is the preservation of the framework’s structural integrity, crystallinity, and porosity. In addition to enhancing functionality, PSM enables the incorporation of specialized recognition elements, such as chiral sites, thereby expanding the applicability of MOFs in advanced biomedical and sensing applications. Owing to its mild reaction conditions, operational simplicity, versatility, and precise control over surface properties, PSM has become an effective strategy for engineering multifunctional MOFs. Nevertheless, these modifications may occasionally introduce structural defects or partially reduce crystallinity, which should be carefully considered during material design [15]. Several surface-engineering strategies have been developed to enhance the biological performance of MOFs and optimize their suitability for nanotheranostic applications. Among the most widely used approaches, polyethylene glycol (PEG) modification improves colloidal stability, biocompatibility, and blood circulation time, thereby reducing premature clearance by the immune system [37]. Lipid bilayer coatings can further enhance structural stability and facilitate targeted delivery, while tumor cell membrane coatings provide biomimetic properties that promote immune evasion and homologous tumor targeting [38, 39]. In addition, covalent surface functionalization offers a versatile platform for introducing a wide range of bioactive molecules and targeting ligands, greatly expanding the functionality of MOFs [40]. Collectively, these surface-modification strategies enable the rational design of MOFs with improved biological interactions, targeting efficiency, and therapeutic performance, supporting their development as next-generation nanotheranostic platforms.

MOFs in targeted drug delivery

MOFs have attracted significant attention as advanced drug delivery systems (DDSs), particularly in the field of cancer therapy. Their highly porous structures allow therapeutic agents to be incorporated either after MOF synthesis or directly during framework formation, providing considerable flexibility in drug-loading strategies [41]. Compared with many conventional nanocarriers [42–44], MOFs generally offer substantially higher drug-loading capacities and encapsulation efficiencies, owing to their exceptionally large surface areas and tunable pore architectures [45, 46]. Another key advantage of MOFs is their ability to respond to a variety of biological and external stimuli. In the tumor microenvironment (TME), factors such as acidic pH, altered redox balance, and enzyme activity can trigger drug release, while external stimuli including light, heat, and magnetic fields provide additional control over therapeutic activation. These stimulus-responsive characteristics enable precise and localized drug delivery, improving treatment efficacy while minimizing off-target effects and systemic toxicity [47] (Table 1).

Table 1.

Summary of stimuli-responsive MOFs for targeted drug delivery

Stimulus Type	MOF Type	Cargo	EE% ٭, LC% ٭	Particle Size	Response Behavior	Ref.
pH	H2L*-MOFs	DOX	-	~ 45 nm	DOX release: 53% (10 h, pH 7.2) and 80% (10 h, pH 5.1)	[56]
	MIL-100(Fe)	Piperine	EE: 95 ± 3%, LC: 11.02%	98 _ 27.83 nm	Only 25% released over 14 days at pH 5.0 and 7.2% at pH 7.4	[57]
	ZIF-8	5-Fluorouracil (5-FU)	271.41 ± 21.94 mg/g	-	0.66 mg more 5-FU at pH 5.5 than 7.4 for at least 72 h	[58]
	MIL-100(Fe)	Collagenas, Methotrexate (MTX)	EE of collagenase: 91.74%, MTX: 50.3%,	800 nm	MTX release: 50% (48 h, pH 7.4), about 24% (48 h, pH 5), Collagenase release: 26.9% at pH 5.0 after 24 h (8% less than pH 7.4)	[59]
	Ca-Gly-Maltose BioMOF	Prodigiosin (PG), Simvastatin (SIM)	For co-loading; EE of PG: 98.3 ± 1.24%, SIM: 66.25 ± 2.67%	In coated BioMOFs: 181 ± 7.1 nm	~ 35% for PG within 90 min at pH = 5.0; ~54% for SIM after 60 min at pH = 5.0,	[60]
Light	Zr-TCPP	Gambogic acid	EE = 38.4 ± 0.6%, LC = 1.04 ± 0.01%	141.8 nm (PDI 0.35)	54.2 ± 1.1% in 24 h at pH = 5.5; 22.2 ± 1.1% at pH = 7.4.	[61]
Temperature	ZJU-801	Diclofenac	LC = 41.7%.	200 nm	The release rate of 60 °C was approximately 3.4 times higher than that at 37 °C and almost 10.3 times higher than that at 25 °C.	[62]
Enzyme	UiO-66	DOX	EE = 11%, LC = 5.5%	198 ± 4 nm (for bare particles)	Value of ~ 73% after 48 h, while the cleavage of PEG was quantitative; in the absence of ALP, resulting in less than 10% after 72 h	[37]
Redox	MOF-199	Disulfiram	LC = 4.9%	~ 100 nm	GSH-triggered release enhances chemotherapy by generating •OH and depleting GSH.	[63]

٭H₂L = Bis (2, 20-bipyridy) (5, 50-di-p-benzoicacid-bipyridinyl) ruthenium (II) dichloride

*EE%=Encapsulation Efficiency (%) =Amount of encapsulated drug/Initial drug×100

٭LC%=Loading Capacity (%) =Amount of encapsulated drug/Total NPs×100

pH-sensitive MOFs

pH-responsive MOFs take advantage of the acidic TME to achieve selective and controlled drug release. Among them, ZIF-8 is one of the most widely investigated systems due to its excellent stability under physiological conditions and rapid degradation in mildly acidic environments. Composed of Zn²⁺ ions and 2-MIM linkers, ZIF-8 undergoes protonation-induced framework disassembly at acidic pH, triggering the release of encapsulated therapeutics. For instance, Yan et al. developed a ZIF-8-based prodrug nanoplatform that enabled targeted and pH-responsive delivery of doxorubicin (DOX) to tumor tissues [48].

Light-sensitive MOFs

Light-responsive MOFs offer precise and non-invasive control over drug release through external photoactivation. Among these systems, Tetrakis(4-carboxyphenyl) porphyrin (TCPP)-based MOFs have attracted considerable attention because of their strong fluorescence and photodynamic properties [49]. Upon light irradiation, the excited TCPP ligand generates ROS, particularly singlet oxygen, which can destabilize the MOF structure and trigger the release of encapsulated therapeutics. This unique behavior enables the simultaneous integration of PDT, PTT, and controlled drug delivery [50]. For example, Li et al. developed an Au nanostar-guided Zr-TCPP MOF that synergistically enhanced both PDT and PTT efficacy [49].

Temperature-sensitive MOFs

Thermoresponsive MOFs enable controlled drug release through temperature-induced disruption of guest–host interactions and weakening of metal–ligand coordination bonds [51]. As temperature increases, structural changes within the framework can promote degradation and trigger the release of encapsulated therapeutics [52]. For example, MOFs constructed with 4-carboxycinnamic acid (H₂CCA) undergo thermal destabilization due to the rigid conjugated structure of the ligand, which efficiently transfers thermal stress to coordination bonds. This process results in framework collapse, ligand degradation, metal ion release, and the subsequent liberation of loaded cargo, highlighting the potential of thermoresponsive MOFs for temperature-controlled drug delivery applications [53].

Redox-sensitive MOFs

Redox-responsive MOFs exploit the elevated glutathione (GSH) levels commonly found in the TME to achieve selective drug release. In these systems, disulfide-containing linkers are cleaved by intracellular reducing agents, leading to framework disassembly and cargo release. For example, Zhao et al. developed a redox-sensitive NMOFs composed of Mn²⁺ ions and dithiodiglycolic acid, which efficiently encapsulated DOX. Upon exposure to GSH-rich tumor cells, cleavage of the disulfide bonds triggered nanoparticle (NPs) degradation and controlled drug release, demonstrating the potential of redox-responsive MOFs for targeted cancer therapy [54].

Enzyme-responsive MOFs

Enzyme-responsive MOFs take advantage of disease-associated enzymatic activity to achieve selective and controlled drug release. In these systems, enzyme-cleavable linkages or biomolecular triggers enable cargo release specifically at the target site [55]. For example, Carrillo-Carrión et al. developed an alkaline phosphatase (ALP)-responsive UiO-66 MOF loaded with DOX. In the presence of ALP and ATP, the nanoplatform released approximately 73% of its drug payload within 48 h, whereas only 10% release was observed under ALP-deficient conditions after 72 h, demonstrating the effectiveness of enzyme-triggered drug delivery for site-specific therapy [37].

Monomodal imaging based on MOFs

Medical imaging plays a fundamental role in disease diagnosis, characterization, and treatment monitoring, particularly in cancer, while also enabling real-time tracking of drug-delivery systems and therapeutic responses. Common imaging modalities, including MRI, CT, PET, FL, and PAI, each offer distinct advantages in terms of sensitivity, resolution, and tissue penetration. However, conventional imaging agents often face limitations such as rapid clearance, nonspecific distribution, and potential toxicity [64]. Owing to their tunable composition and highly porous structures, MOFs have emerged as versatile platforms for multimodal imaging. They can efficiently incorporate a wide range of imaging agents while simultaneously carrying therapeutic cargos, improving imaging performance and enabling integrated theranostic applications [65].

Magnetic resonance imaging (MRI)

MRI is a noninvasive clinical imaging modality that provides high-resolution anatomical and physiological information based on the interactions between external magnetic fields, radiofrequency waves, and hydrogen protons in soft tissues [65]. Contrast agents are used to enhance MRI signals by modulating the longitudinal (T₁) and transverse (T₂) relaxation rates of water protons; however, conventional agents such as Gd³⁺ and Mn²⁺ chelates and superparamagnetic iron oxides (SPIONs) are limited by high dosage requirements, poor solubility, and short circulation times [66].

MOFs have emerged as promising MRI contrast platforms due to their ability to incorporate paramagnetic metal ions or encapsulate magnetic NPs, enabling effective T₁ and T₂ contrast enhancement [64]. MOF-based probes generally exhibit higher longitudinal relaxivity than small-molecule agents, while iron-based MOFs, including MIL-88 A(Fe), offer strong T₂ contrast with low toxicity. In vivo studies demonstrate their imaging efficacy, exemplified by a Gd/DTPA/MOF-808/PANI nanoprobe achieving high r₁ relaxivity in breast cancer models. Overall, the high magnetic ion LC of MOFs supports strong signal enhancement at low doses and facilitates dual T₁/T₂ imaging within a single platform [67].

Computed tomography (CT) imaging

CT is a tomographic imaging technique that provides 3D visualization of internal structures based on X-ray absorption and transmission. High atomic number (high-Z) elements are commonly used as contrast agents to enhance tissue contrast. X-ray scintillating MOFs constructed from hafnium (Hf) (IV) (Z = 72) or Zr (IV) (Z = 40) clusters act as antennas, absorbing X-ray photons and generating fast electrons via the photoelectric effect. These electrons excite anthracene-based emitters in the MOF through inelastic scattering, producing detectable visible photons [65].

NMOFs can preferentially accumulate in tumors via the enhanced permeability and retention (EPR) effect, and their porous architecture allows high loading of high-Z elements, making them effective CT contrast agents. Notably, Hf-MOFs demonstrated superior CT contrast even at lower doses, potentially minimizing patient radiation exposure [68]. In addition, gold (Au)- and bismuth (Bi)-functionalized MOFs have also been employed as CT contrast agents [69]. Compared to iodinated compounds, which often cause nephrotoxicity, MOF-based CT probes offer improved biodistribution, longer retention, and enhanced tumor-specific accumulation, although the potential toxicity of heavy metals still warrants careful evaluation on a case-by-case basis.

Positron emission tomography (PET)

PET is a nuclear imaging technique that uses positron-emitting nuclides to visualize metabolic processes in the body. PET offers deep tissue penetration, high sensitivity, low dose requirements, and strong quantitative capability. Common PET contrast agents include ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁶⁴Cu, ⁶⁸Ga, and ⁸⁹Zr, but they often face limitations such as short half-lives and low specificity in clinical applications [70].

MOFs enable intrinsic radiolabeling by either incorporating radionuclides into the framework or chelating them on the surface, supporting versatile in vivo PET imaging of DDSs. For example, Cai et al. developed a Zr-based UiO-66 MOF labeled with ⁸⁹Zr, PEGylated, and conjugated with an F3 peptide targeting nucleolin on breast cancer cells. Upon DOX loading, PET imaging in mice demonstrated efficient tumor accumulation of the radiolabeled MOFs [30]. Other radionuclides, such as ⁶⁴Cu [71] and ⁶⁸Ga, can also be integrated using MOF chelators. MOFs’ ability to carry multivalent radiolabels enhances PET sensitivity and enables integration with other imaging modalities (e.g., PET/CT) in a single theranostic platform [72].

Optical imaging (OI)

OI, as a widely used diagnostic imaging modality, involves the conversion of light into fluorescent or phosphorescent signals by imaging agents to convey information about organs, tissues, or cells within biological systems. This technique offers advantages including facile operation, high sensitivity, and high spatial resolution [65]. Luminescent MOFs have emerged as versatile platforms for OI through the incorporation of fluorescent dyes, lanthanide ions, or luminescent NPs, with their well-defined structural features contributing to enhanced fluorophore stability [11]. In particular, lanthanide-based MOFs and MOF– Upconversion Nanoparticle (UCNP) NPs hybrids have been reported to extend emission into the visible and near-infrared (NIR) spectral regions [73]. Table 2 summarizes the key differences between traditional and MOF-based contrast agents in terms of biocompatibility, stability, signal strength, and multifunctionality.

Table 2.

Comparison of conventional and MOF-based contrast agents across imaging modalities

Aspect	Conventional agents	MOF-based agents
MRI efficiency	Gd³⁺ chelates (T₁): R*₁ ≈ 4–5 mM⁻¹·s⁻¹; SPIONs for T₂ contrast.	Gd-MOFs: R₁ ≈ 13–30 mM⁻¹·s⁻¹; Mn-MOFs similar; some MOFs enable dual T₁/T₂ imaging [64].
CT efficiency	Iodine-based agents with moderate contrast Hounsfield units (HU), rapid renal clearance.	High-Z MOFs (e.g., Hf-, Ta-MOFs) provide significantly higher HU and prolonged retention [64].
PET sensitivity	Radiotracers like ¹⁸F-FDG are highly sensitive but have short half-lives.	MOFs labeled with ⁶⁴Cu or ⁸⁹Zr enable multivalent binding and tunable half-life for enhanced uptake [30].
Optical signal	Dyes such as Indocyanine green (ICG) and FITC suffer from photobleaching and quenching.	MOFs protect dyes (e.g., FITC@MOF) and enable integration of UCNP or Quantum Dot for stable fluorescence [64].
Targeting ability	Mostly passive; lacks intrinsic targeting mechanisms.	MOFs can be surface functionalized with ligands (e.g., antibodies, peptides) for active targeting [76]
Multimodality	Typically requires co-injection of multiple agents for different modalities.	MOFs can combine multiple imaging modalities (e.g., MRI + FL + CT) within a single nanoplatform [11]
Toxicity profile	Gd poses a risk of nephrogenic systemic fibrosis; iodine is nephrotoxic.	MOFs with biocompatible metals (e.g., Zr, Fe) show lower toxicity; they may reduce dose via high payload [64]
Stability & clearance	Fast renal clearance; limited control over biodistribution or degradation.	MOF degradation can be tailored (e.g., pH-sensitive); PEGylation and size control influence clearance.

*R: resolution

Photoacoustic imaging (PAI)

PAI is a noninvasive and nonionizing biomedical imaging modality that has been developed in recent years. When biological tissue is irradiated with a pulsed laser, absorbed optical energy is converted into localized thermal expansion, generating US waves within the light-absorbing regions of the tissue. PAI integrates the high contrast and selectivity of OI with the deep tissue penetration of US imaging, thereby producing images with high spatial resolution and contrast [74]. In principle, this technique mitigates the effects of optical scattering and overcomes the conventional “soft limit” associated with high-resolution OI [75].

Multimodal imaging based on MOFs

Monomodal imaging modalities, including OI, MRI, CT, PET, and PAI, each offer distinct advantages for cancer diagnosis and monitoring. OI provides high sensitivity and resolution but is limited by shallow tissue penetration, whereas MRI offers excellent spatial resolution and deep tissue imaging with relatively low sensitivity. CT enables high-resolution anatomical imaging but exhibits limited soft-tissue contrast, while PET provides exceptional sensitivity and quantitative capability despite challenges related to short radionuclide half-lives and operational complexity. PAI combines noninvasiveness, high resolution, and satisfactory tissue penetration, although its imaging depth and signal coverage remain constrained [77]. Collectively, these limitations highlight the need for complementary imaging approaches to achieve more comprehensive disease characterization. Consequently, single-modality imaging often fails to capture the comprehensive anatomical, functional, and molecular information required for accurate disease characterization. To address these limitations, multimodal imaging theranostics have been developed by integrating two or more complementary imaging techniques within a single platform. Such systems combine the strengths of individual modalities while overcoming their respective weaknesses, enabling more comprehensive tumor visualization, improved diagnostic accuracy, real-time therapeutic monitoring, and enhanced precision in cancer management [78]. For example, Ji et al. developed a lanthanide-based Eu-MOF/GelMA composite hydrogel for dual-modal fluorescence (FL) and CT imaging (Scheme 1A). The intrinsic luminescence of Eu³⁺ enabled FL, while the high X-ray attenuation of europium provided effective CT contrast. Incorporation of the Eu-MOF into a photocrosslinked GelMA matrix enhanced signal retention and localized imaging performance. Ex vivo and in vivo studies demonstrated strong fluorescence signals, enhanced CT visibility, and stable localization at injection sites, enabling accurate tracking of the implanted material. By leveraging the inherent optical and radiographic properties of the lanthanide MOF, this platform achieved complementary FL/CT imaging within a single system, highlighting the potential of lanthanide-based MOFs for multimodal diagnostic and image-guided biomedical applications [79].

Scheme 1.

(A) Schematic illustration of the components of the Eu-MOF/GelMA composite hydrogel and its application in fluorescence/CT dual-modal imaging, Adapted from ref [79]. with permission, (B) Schematic of procedure of RPZC and therapeutic mechanism, Adapted from ref [80]. with permission

Huang et al. reported a multifunctional ZIF-based nanoplatform (RPZC) designed for tumor-targeted multimodal imaging through the integration of a cobalt-based zeolitic imidazolate framework, chlorin e6 (Ce6), polydopamine coating, and RGD peptide functionalization (Scheme 1B). The platform exhibited prolonged blood circulation and enhanced tumor accumulation owing to its biomimetic surface engineering and active targeting capability. The intrinsic fluorescence of Ce6 enabled FL for real-time visualization of NPs biodistribution and tumor localization, while the cobalt-containing framework contributed additional imaging functionality for multimodal diagnostic applications. In vivo studies confirmed efficient tumor targeting, high imaging contrast, and dynamic monitoring of NPs distribution, highlighting the potential of engineered MOF nanoplatforms for precision molecular imaging and image-guided cancer diagnosis [80].

Yang et al. developed a defect-engineered iron-based MOF nanoplatform, Cypate@MIL-53/PEG-Tf (CMNP-Tf), for multimodal tumor imaging by integrating near-infrared fluorescence (NIRF), PAI, and MRI. The incorporation of cypate within the MIL-53 framework enhanced dye stability and reduced photobleaching while preserving its optical properties, enabling robust NIRF and PAI performance. Surface modification with PEG and transferrin (Tf) improved colloidal stability, prolonged circulation time, and promoted tumor-specific accumulation through transferrin receptor-mediated targeting. Meanwhile, the Fe-based MOF provided intrinsic MRI contrast capability, allowing complementary anatomical and functional imaging. In vivo studies demonstrated efficient tumor localization, strong photoacoustic signals, significant T1-weighted MRI enhancement, and favorable biocompatibility without observable systemic toxicity. This work highlights the potential of defect-engineered and surface-functionalized MOFs as versatile multimodal imaging platforms for precise cancer diagnosis and image-guided biomedical applications [81]. Table 3 summarizes representative examples of MOFs employed in monomodal and multimodal imaging platforms.

Table 3.

Representative monomodal and multimodal imaging based on MOFs

Imaging Modality	MOF Type	Cargo/Agent	Surface Modifier	Model (in vitro/in vivo)	Particle Size (nm)	Contrast Agent(s)	Key Results & Observations	Ref.
FL	Fe-MOF	BSO*, oxaliplatin prodrug	Lipid bilayer (DOPE-SMCC)	4T1 cells – in vivo	170 × 70	DiR*	Strong tumor accumulation; successful targeting with RGD modification.	[82]
MRI, PAI, CT	MIL-88(A)	Au	PEG	Multiple tumor cell lines – in vivo	20–150	PAI: Au NRs, MRI: Fe (MIL-88(A))	Low toxicity, deep tissue imaging, and enhanced spatial resolution for glioma detection.	[83]
MRI, FL	MIL-53-NH₂	5-FU, 5-Carboxylfluorescein (5-FAM)	Folic acid (FA)	MGC-803 cells – in vivo	~ 120	FL: 5-FAM, MRI: Fe (MIL-53)	High biocompatibility, enhanced uptake, and effective tumor growth inhibition.	[84]
FL	UiO-67-(NH)₂	5-FU, PMT*, 5-FAM	FA	A549 cells – in vivo	~ 178	FL: 5-FAM	Co-loading and targeted delivery, FL, to enhance therapy.	[85]
FL	ZIF-8	ICG	None	A549 cells – in vivo	166 ± 17	FL: ICG	Real-time siRNA delivery tracking, FL switch-on for imaging.	[86]
MRI	MIL-101(Fe)	Sorafenib	None	HepG2 cells – in vivo	~ 200	MRI: Fe (MIL-101)	MRI capability, peroxidase-like activity, and ferroptosis induction in HepG2.	[87]
OI	ZIF-8	DOX	None	4T1 cells – in vivo	~ 110	Cy5	In vivo multimodal OI of MOF distribution.	[88]
MRI	ZIF-8, ZIF-67	Iron oxide, Quercetin	None	MDA-MB-231, MCF-7 – in vivo	~ 450	MRI: IO NPs	Enhanced MRI contrast; targeted delivery via FA ligand.	[89]

*BSO= Buthionine sulfoxid amine

*DiR = 1,1-Dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide

*PMT= Pemetrexed

Monomodal therapies based on MOFs

Practical therapeutic modalities, including phototherapy (PT), sonodynamic therapy (SDT), radiotherapy (RT), CDT, immunotherapy, and starvation therapy, offer alternative strategies for cancer treatment [90]. However, their clinical effectiveness is often limited by insufficient therapeutic efficacy, severe side effects, and poor targeting [91]. MOFs can deliver a wide range of therapeutic agents—such as drugs, enzymes, proteins, photosensitizers (PSs), PTT agents, and antibodies—to tumor sites, thereby enhancing therapeutic efficiency and reducing adverse effects [70]. In addition, the incorporation of functional nanocomponents, including Au NPs, Fe₃O₄ NPs, CuS NPs, and polypyrrole NPs, into MOFs has enabled the development of intelligent, multifunctional nanoplatforms for precise cancer therapy [92]. This section outlines the application of MOF-based nanocomposites as smart nanoplatforms for tumor treatment using single-modality strategies, including PTT, SDT, RT, CDT, immunotherapy, and starvation therapy (Table 4).

Table 4.

Representative monomodal and multimodal therapies based on MOFs

Therapeutic Modality	MOF Type	Cargo	Modification	Study Type	Ref.
PTT, PDT	Fe-TCPP	Tirapazamine (TPZ)	Cell membrane	In vivo	[115]
PTT, PDT, CDT	Ce-TCPP	ICG, Mn	–	In vitro	[116]
PTT	ZIF-8	DOX	HA*	In vitro	[117]
PTT, PDT	Fe-TCPP	MTX	HA	In vivo	[118]
PDT	Fe-TCPP	–	–	In vitro	[119]
CDT	Hf-DBA	Horseradish peroxidase (HRP)	–	In vitro	[120]
CDT	ZIF-8	DOX	PDA, HA	In vivo	[121]
CDT	ZIF-67	Ag₂O₂	–	In vivo	[122]
PTT	ZIF-8	Cy, BNN6	–	In vivo	[123]
SDT, Starvation	Gd-TCPP	GOx	NC-FAA*	In vivo	[124]
PDT	PCN-224	DOX	HA	In vivo	[125]
SDT	ZIF-8	Tirapazamine, Ce6	Cell membrane	In vivo	[126]
PTT	ZIF-8	Polyoxometalate, Chloroquine	HA	In vitro	[127]
PDT	PCN-224	DOX	MUC1 aptamer	In vivo	[128]
CDT, RT	UiO-type, Hf-MOF	–	–	In vivo	[129]
CDT, SDT	Cu-MOF	AIPH*	–	In vivo	[130]
PDT	Hf-QC	ZnP	–	In vivo	[131]
PA	ZIF-8	Bovine serum albumin (BSA), HRP, TMB	–	In vivo	[132]

* NC-FAA: 2-(5-norbornene-2-carbaldehyde)−5-fluorobenzoic acid

* HA: Hyaluronic acid

* AIPH: Azo initiator 2,2′-azobis(2-(2-imidazolin-2-yl)-propane) dihydrochloride

Phototherapy (PT)

PT eliminates tumor cells primarily through PDT, which generates ROS, and PTT, which induces localized hyperthermia. PDT is a light-activated modality that employs PSs and molecular oxygen to induce tumor cell apoptosis and tissue damage via type I pathways, which generate ROS through electron transfer, and type II pathways, which produce cytotoxic singlet oxygen through energy transfer [93]. Despite advantages such as minimal invasiveness, high selectivity, and reduced side effects compared with chemotherapy and RT, PDT remains limited by photosensitizer instability, shallow light penetration, and oxygen dependence. MOFs have been developed as intrinsic photoresponsive agents or as carriers for exogenous PSs [94]; porphyrin-based MOFs (e.g., PCN-224) exhibit inherent PDT activity [95], while their porous structures enable cargo loading to alleviate tumor hypoxia [96].

In contrast, PTT induces tumor necrosis by converting NIR light into heat, benefiting from deeper tissue penetration, oxygen independence, and the higher sensitivity of cancer cells to hyperthermia [97].PTT typically employs light within the first (750–1000 nm) and second (1000–1700 nm) NIR biological windows due to their high tissue penetration depth and low absorption by biological tissues [98]. However, limited tumor specificity and restricted penetration continue to constrain its therapeutic efficacy. MOF-based nanoplatforms play a critical role in addressing these limitations owing to their high LC and facile integration with PTT agents, thereby enabling enhanced and synergistic phototherapeutic outcomes [99, 100].

Sonodynamic therapy (SDT)

SDT is an emerging technique that uses US to activate sonosensitizers for ROS generation in deep tissues. MOFs serve as excellent carriers or scaffolds for sonosensitizers such as porphyrins or titanium dioxide (TiO₂) nanosheets. Upon US irradiation, these MOF-based platforms generate singlet oxygen and other ROS, with the porous matrix enhancing oxygen diffusion and improving therapeutic efficacy. The advantages include enhanced stability, controlled biodistribution, and high ROS yield [101].

Radiotherapy (RT)

RT uses high-dose ionizing radiation to eliminate cancer cells, benefiting from deep tissue penetration. Its clinical efficacy is limited by low tumor specificity, poor radiation absorption, and high-dose requirements, which can cause systemic toxicity and long-term complications, while repeated RT may induce tumor resistance [102]. MOFs enhance RT by serving as radioenhancers. High atomic number (Z) elements in MOFs, such as Hf, Zr, Ta, or Au, efficiently absorb X-rays, generate secondary electrons, increase ROS production, and promote DNA damage in tumor cells, potentially reducing the required radiation dose [103].

Chemodynamic therapy (CDT)

CDT utilizes the endogenous TME—specifically, elevated hydrogen peroxide (H₂O₂) and low pH—to initiate Fenton or Fenton-like reactions that generate highly toxic hydroxyl radicals (^•OH) [104]. MOFs are well-suited for CDT as they often contain catalytically active metals like Fe²⁺, Cu²⁺, or Mn²⁺. These ions are released selectively in acidic tumor environments, where they react with H₂O₂ to produce localized ROS, thereby minimizing systemic toxicity [105].

Immunotherapy

Immunotherapy activates or enhances the patient’s immune system to target tumor cells, offering advantages over conventional treatments, including reduced side effects, broad applicability, and immune memory. Despite notable progress, its clinical use is limited by inflammatory responses, the immunosuppressive TME, and variable patient responses [106]. MOFs are employed as nanocarriers in immunotherapy to deliver therapeutic agents such as antigens, adjuvants, and immunomodulators, thereby enhancing efficacy. Some MOFs function as in situ cancer vaccines, while others are designed to co-deliver immune checkpoint inhibitors, such as anti-PD-1 or anti-CD47, to counteract tumor immune evasion [107].

Starvation therapy

Tumor cells exhibit elevated nutrient and energy demands due to metabolic dysregulation and preferential reliance on glycolysis, as described by the Warburg effect, leading to increased glucose consumption. On this basis, glucose deprivation has been explored as a tumor starvation strategy. GOx has been widely applied to deplete glucose; however, its clinical efficacy is limited by poor stability and environmental sensitivity [108]. MOFs have been proposed as effective carriers for GOx, as they protect enzymatic activity, enable controlled release within the TME, and facilitate glucose depletion accompanied by the generation of cytotoxic byproducts such as H₂O₂, ultimately promoting cancer cell death [109].

Multimodal therapies based on MOFs

Although MOF-based nanoplatforms have demonstrated promising therapeutic efficacy in cancer treatment, single therapeutic modalities remain constrained by inherent limitations [110]. Conventional approaches such as radiotherapy and chemotherapy often cause significant systemic toxicity, whereas chemodynamic and starvation therapies depend heavily on the availability of endogenous H₂O₂ and oxygen within the TME. Similarly, phototherapy offers precise and minimally invasive treatment but is restricted by limited light penetration depth, while immunotherapy can be associated with excessive inflammatory responses and variable clinical outcomes. To overcome these challenges, combination therapeutic strategies that integrate two or more treatment modalities within a single MOF-based platform have gained increasing attention [111]. By exploiting complementary mechanisms of action, these synergistic systems can enhance antitumor efficacy, reduce therapeutic dosages and adverse effects, and effectively address the limitations of individual therapies, often achieving superior outcomes compared with monotherapy [112]. For example, Sun et al. developed a Mn-porphyrinic MOF nanoreactor (GOx@Mn-TCPP) that combines glucose starvation therapy, chemodynamic therapy, and photodynamic therapy through a tumor-responsive catalytic cascade. GOx-mediated glucose consumption generated H₂O₂, while Mn³⁺/Mn²⁺ redox cycling depleted intracellular glutathione and catalyzed Fenton-like hydroxyl radical production. Simultaneously, the TCPP ligand generated singlet oxygen under laser irradiation, and Mn-TCPP-mediated oxygen generation alleviated tumor hypoxia, thereby enhancing PDT efficacy. Collectively, the synergistic modulation of tumor metabolism, redox homeostasis, and ROS amplification resulted in significant tumor suppression and favorable biosafety, highlighting the potential of multifunctional MOF nanoreactors for integrated cancer therapy [113].

Furthermore, Zhang et al. developed an Fe-based porphyrinic MOF nanoplatform (Fe-MOF@Ir/GOx) that integrates glucose depletion, nanozyme catalysis, and photodynamic therapy through a TME-responsive ROS amplification cascade. The incorporation of Ir NPs and GOx within the Fe-TCPP framework enables GSH-triggered activation, where GOx-mediated glucose oxidation generates H₂O₂ and induces metabolic starvation. Concurrently, Ir NPs enhance oxygen generation and catalytic ROS production, while Fe²⁺ released from the MOF promotes Fenton reactions and the porphyrin ligand generates singlet oxygen under irradiation. This synergistic catalytic strategy amplifies oxidative stress, overcoming limitations associated with hypoxia, insufficient H₂O₂ availability, and antioxidant defense, highlighting the potential of MOF-based nanoreactors for advanced TME-responsive cancer therapy [114]. An overview of MOF-based monomodal and multimodal therapeutic and imaging strategies is presented in Table 4.

MOF‑based nanotherapeutics

MOF-based theranostics leverage the compositional tunability of MOFs to integrate multimodal imaging and therapeutic functions (Table 5). A recent study demonstrated that multifunctional MOF-based nanoplatforms can precisely modulate tumor redox homeostasis by integrating TME-responsive activation with multiple synergistic therapeutic mechanisms (Scheme 2). A representative example is the ultrathin AuTPyP–Cu coordination MOF nanosheet, which undergoes pH- and US-responsive degradation within the TME, resulting in the controlled release of Cu²⁺ and Au(III)-porphyrin species. The released Cu²⁺ is reduced by intracellular GSH to Cu⁺, initiating Fenton-like reactions that generate highly cytotoxic hydroxyl radicals while simultaneously depleting GSH, thereby weakening the cellular antioxidant defense system. Concurrently, the Au(III) component inhibits the thioredoxin reductase/thioredoxin (TrxR/Trx) pathway, further disrupting redox homeostasis and promoting intracellular ROS accumulation. Beyond oxidative stress amplification, copper-mediated mitochondrial dysfunction activates the FDX1-dependent cuproptosis pathway, providing an additional mechanism for tumor cell elimination.This integrated approach highlights the emerging role of MOFs as multifunctional theranostic platforms that simultaneously amplify oxidative stress, disrupt antioxidant defenses, and induce regulated cell death, thereby significantly enhancing the efficacy of precision cancer therapy [133].

Table 5.

Representative MOF‑based nanotherapeutics

Type of MOF	Type of diagnostic	Type of Therapy	MOF cargo	Modifier	Synthesis Method	LE%, LC%	Model (in vitro/in vivo)	size	ref.
ZIF-8	MRI, PA	PTT	DOX	PDA, Mn ions and PEG	One-pot	LC: 18.9%	PC-3 cells-in vivo	~ 206 nm	[141]
	FL	PDT	PSs	Poly(methyl methacrylate) and (SS-mPEG)	-	TBD and Ce6 at W% = 21.4% and 24.0%.	4T1 cells-in vivo	Over 200 nm	[142]
	FL	PTT	ICG, Dihydroartemisinin (DHA)	-	One-pot	LC: DHA: 16.7% and ICG: 10.9%,	HepG2 cell -in vivo	137.5 ± 20.5 nm	[143]
	FL	PTT, PDT	Ce6	BSA	-	EE :53.5 ± 3.2% and LC :32.1 ± 3.3%.	MNNG/HOS cells-in vivo	100.2 nm	[144]
	MRI	PDT	ICG	DSPE-PEG + EM	One-pot	EE: 60%	4T1 cells -in vivo	100 nm	[145]
	CT, PAI, FL	PTT	LCG, Cisplatin (DDP), BYL719	PEG, PAA	-	LC of BYL719 and DDP = 24.3 ± 1.3% and 7.7 ± 0.9%,	EphA2 cells -in vivo	123.7 ± 8.6 nm	[146]
	IRI, PAI, FL	PTT, PDT	DOD, ICG	Polyvinylpyrrolidone (PVP)	One-pot	-	4T1 cells-in vivo	131.9 nm	[147]
Zn-MOFs	FL, MRI	immunotherapy	CD22 shRNA	PEI + EM	-	-	bEnd 3 cells- in vivo	-	[148]
ZIF-90	FL	PDT	DOX, IR780	HA	Microfluidics-based	LC: IR780 = up to 14.3 wt %, LC: DOX = 28.8 wt %	HeLa cells-in vivo	126 nm	[149]
PCN-224	FL, PT	PTT, PDT	GA	LP	-	EE: 38.40 ± 0.57%, LC = 1.04 ± 0.01%	RAW264.7 cells- in vivo	190.1 ± 0.24 nm	[61]
	FL	PDT, immunotherapy	BMS-202	HA, PEG	Solvothermal	LC:25.02%	L929 and 4T1 cells-in vivo	∼125 nm	[150]
	PTI, FL, PAI	PTT, PDT	-	-	One-pot	-	4T1 cells-in vivo	127.8 nm to 153.7 nm	[151]
	PET	PDT	-	Au	Solvent-assisted self-assembly	-	U87MG cells-in vivo	∼126.4 nm	[152]
	MRI, FL	PDT	Ce6 and Rose Bengal (RB)	-	Solvothermal	EE of Ce6 and RB > 80%	4T1 cells-in vivo	216.0 ± 7.3 nm	[153]
	PET	PDT	DOX	Py − PGA-PEG	Solvothermal	1 mg DOX/mg UiO-66	MDA-MB-231 and L929 cells-in vivo	255 ± 10 nm	[30]
	FL	CDT, PTT	-	-	Hydrothermal	-	7702, 4T1, and Huh7 cells-in vivo	510 nm	[154]
	Immunofluorescent imaging	SDT	-	-	Solvothermal	-	H22 cells and 4T1 cells- in vivo	70.0 nm	[155]
	Immuno fluorescence imaging	PTT	DDP	HA	Solvothermal	-	cancer cell line (4T1)-in vivo	-	[156]
Fe-TCPP	MRI, FL	PDT	-	BSA, Sulfadiazine	Modified method	-	4T1 cells- in vivo	122 nm	[157]
	FL	PDT	-	-	One-pot	-	CT26. WT cells and BNL. CL2- in vivo	250 nm in 100 nm	[158]
	MRI, FL	CDT, PDT	-	HA	Solvothermal	-	4T1 cells-in vivo	160 ± 33, 90 ± 12 nm	[159]
MIL (Fe)	MRI, CT, FL	CDT	FePt (S), FePt (R)	-	Solvothermal	-	4T1 cells-in vivo	180 nm	[160]
	MRI, FL	PTT	urokinase Plasminogen activators	-	Hydrothermal	LE% = 51.4% and LC% =38.7%	HSF and HUVECs cells -in vivo	~ 100 nm	[161]
	MRI	PTT	CH4T	SCM-PEG-SCM	-	LC = 33.5%	U87MG cell-in vivo	~ 132.2 nm	[162]
	FL	Starvation, CDT	DOX, Gox	NH2-PEG2000	Solvothermal	-	4T1 cells-in vivo	150 nm	[163]
	MRI	magnetic hyperthermia (MHT)	DOX	C-PVP	MW	EE: 70%	CAL27 cell-in vivo	-	[164]
	FL	CT, PTT, PDT	ICG and DOX	HA	-	EE% of ICG and DOX: 88.96% and 87.84%, LC% :3.58% and 21.69%.	cancer-mice study	100 nm	[165]
	MRI, PAI	PTT, CDT	-	Mn-based PBA (K2Mn Fe(CN)6)	-	-	4T1 cells-in vivo	144.9 to 217.5 nm	[166]
	Immune fluorescence images	CDT, RT-RDT, immunotherapy	-	-		-	MC38 cells-in vivo	81.6 ± 3.6 nm	[167]
	FL	immunotherapy	TPL	BSA	One-pot and ultrasonication	LC = 36.2% and EE = 81.4%	B16F10-luc cells- in vivo	200 nm	[168]
	FL	CDT	DOX	-	Solvothermal	EE : 82.61% LC: 4.52%,	4T1 cells- in vivo	~ 174.6 nm	[169]
	MRI, CT, PAI	PTT	DOX	HA	-	LC = 23.56%.	4T1 cells-in vivo	160.24 nm	[170]
	Immuno fluorescence imaging	Immunotherapy, PDT	RSL3	HA	Hydrothermal	EE: ~91.0 ± 3.1%	253 J, 5637 and SV-HUC-1 cells-in vivo	-	[171]
	SPECT imaging	CDT	99mTc-DOX	-	Two-step	EE: 98% after 4 h of stirring	MCF-7- in vivo	94.8 nm	[172]
	FL	CDT	Acriflavine	COOH-PEG-COOH	Solvothermal	LC: 48.7%, and EE:73%,	Hepa1-6- in vivo	-	[173]
Hf-Mn-TCPP	CT, MRI, PAI	PTT, RT	-	-	Modified solvothermal	-	4T1 cells- in vivo	~ 215 nm,	[174]
	MRI, CT, PAI	PTT, RT	-	-	One-pot hydrothermal	-	HeLa cells-in vivo	93.4 nm in 32.3 nm	[68]
Mn-MOFs	MRI, FL	PTT		Succinimide–PEG–Mal	One-pot	-	HeLa and 4T1 cells- in vivo	85 nm.	[175]
	MRI, FL	PDT	Ce6	-	One-pot	LC: 32.8 ± 1.3 wt% and EE: 95.5 ± 3.2%.	4T1 cells-in vivo	124 ± 6.2 nm	[176]
Cu-TCPP	MRI, FL	PTT, PDT	-	-	-	-	Saos-2 cells- in vivo	330 nm	[177]
Cu-MOFs	PAI	CDT, SDT	Ce6	-	Solvothermal	LC of Cu2 + and Ce6 = 13.9% and 8.7%	MCF-7 cells-in vivo	260 nm.	[178]
	FL	Starvation	Dox and GOx	-	One-pot	LC = 13.6% to Dox and 3.38% to Gox	A549/Dox cells-in vivo	~ 80 nm	[179]
MIL-125(Ti)	FL	SDT	TPZ	TiO2/C-PEG	Solvothermal	LC: 7.73 ± 0.22%	MCF-7 cells- in vivo	108.5 ± 9.8 nm	[180]
Ti-TCPP	PAI, FL	SDT	-	-	-	-	BxPC-3 cells -in vivo	12.21 ± 1.27 nm	[181]
Gd-MOF	MRI, Immunofluorescence images	MWTT, immunotherapy.	PD-1 inhibitor	SCC7 cell membrane	Hydrothermal	-	SCC7 cell- in vivo	182 nm	[182]

Scheme 2.

Coordination self-assembled AuTPyP-Cu MOF nanosheets with pH/US dual-responsiveness for synergistically triggering cuproptosis-augmented chemotherapy, (a) Overall procedure of the in vivo animal experiments. (b) In vivo T1-MR imaging monitoring of HeLa-bearing mice at 6 h post i.v. injection of PBS and TAT-AuTPyP-Cu NSs. (c) In vivo fluorescence monitoring of targeted accumulation of TAT-AuTPyP-Cu NSs in tumors of HeLa-bearing mice (dosage: 10 mg/kg).

Adapted from ref [133]. with permission

Zheng et al. reported a multifunctional Cu-based MOF nanoplatform that capitalizes on endogenous hydrogen sulfide (H₂S), a characteristic biomarker of colorectal cancer, to achieve precise tumor-specific theranostic performance through TME-responsive activation. Upon exposure to acidic and H₂S-rich tumor conditions, the PEGylated HKUST-1-derived Cu-MOFs undergo structural transformation into CuS NPs while simultaneously releasing DOX, thereby integrating chemotherapy with chemodynamic and photothermal therapy (Scheme 3). The in situ generated CuS not only provides strong PAI contrast for image-guided treatment but also induces copper-dependent regulated cell death (cuproptosis) through modulation of the FDX1/DLAT/DLST signaling axis, resulting in enhanced tumor suppression. This biomarker-activated strategy highlights the potential of intelligent MOF nanoplatforms to integrate molecular imaging, catalytic therapy, and programmed cell death within a single precision theranostic system for cancer treatment [134].

Scheme 3.

Imparting high biosafety to multivariate Cu-MOFs by PSM for synergistic cancer therapy, (a) Schematic illustration for the synthesis of Cu‐MOFs and its PSM, DOX loading, and the its sulfidation into CuS, (b) The in situ reaction of Cu‐MOFs with endogenous H2S initiated PA imaging and combined PTT/cuproptosis/chemotherapy for colorectal cancer treatment. MOFs, (c) In vivo PA images and signal intensities of tumor‐bearing mice subjected to various treatments at 8 h time point, (d) The quantification of PA signals from the tumor site in, (e) Thermal images (f) and corresponding temperature versus time of various groups under 808 nm irradiation at 0.5 W/cm2 for 10 min.

Adapted from ref [134]. with permission.

Guo et al. developed a photo-responsive hollow Fe/Zn-based MOF nanoplatform (F127@ICG@MnCO@MOF, FIM@MOF) that integrates TME-responsive drug release with multimodal imaging and synergistic cancer therapy (Scheme 4A). Constructed from Fe/Zn ions coordinated with terephthalic acid (H₂BDC) and surface-modified with Pluronic F127, the hollow MOF simultaneously encapsulates ICG and the carbon monoxide donor manganese carbonyl (MnCO). Under acidic tumor conditions, the MOF undergoes controlled degradation to release ICG and manganese carbonyl (MnCO). Upon near-infrared irradiation, ICG simultaneously generates singlet oxygen and localized hyperthermia, enabling combined photodynamic and photothermal therapy, while the photothermal effect accelerates MnCO decomposition to achieve spatially controlled carbon monoxide (CO) gas release. The released CO further induces mitochondrial dysfunction and amplifies oxidative stress, thereby enhancing apoptotic tumor cell death. Simultaneously, the nanoplatform provides fluorescence/photoacoustic dual-modal imaging for precise image-guided therapy, demonstrating the potential of multifunctional MOFs for integrating TME responsiveness, gas therapy, multimodal imaging, and synergistic phototherapy in precision cancer treatment [135].

Scheme 4.

(A) Schematic diagram of the synthesis of a light-responsive CO nanoplatform and its application in synergistic photothermal/photodynamic/gas therapy for cancer., Adapted from ref [135]. with permission, (B) The synthetic route of, (a) oxaliplatin prodrug and, (b) PCN-Oxpt/PEG, (c) Schematic illustration of the application of PCN-Oxpt/PEG for combined cancer therapy. Reproduced from the reference [136] with permission

Hu et al. developed a PEGylated Fe(III)-porphyrinic MOF (PCN-Oxpt/PEG) that integrates chemotherapy, chemodynamic therapy, ferroptosis, immunotherapy, and dual-modality imaging within a single TME-responsive nanoplatform (Scheme 4B). Following phosphate-triggered intracellular degradation, the nanoplatform releases Fe³⁺ and an oxaliplatin (IV) prodrug, enabling Fenton-mediated hydroxyl radical generation while simultaneously consuming intracellular glutathione and suppressing GPX4 activity to amplify ferroptosis. In parallel, oxaliplatin induces immunogenic cell death, promoting dendritic-cell maturation, CD8⁺ T-cell activation, macrophage polarization, and IFN-γ secretion, which further downregulates the System Xc⁻ transporter (SLC7A11/SLC3A2) to reinforce ferroptotic cell death. Moreover, the Fe(III)-porphyrin framework enables T1-weighted magnetic resonance and FL, demonstrating the potential of multifunctional MOFs to combine catalytic therapy, immune modulation, ferroptosis, and image-guided precision cancer treatment within a single theranostic platform [136].

Recent studies indicate that biointerfacing capabilities can be enhanced by modifying NPs surfaces with peripheral proteins or cell membranes, enabling the modified NPs to acquire additional characteristics of the source cells. In a recent study, an erythrocyte membrane (EM)-camouflaged ZIF-based MOF nanoplatform (MMCC@EM) was engineered to integrate TME-responsive drug delivery with multimodal imaging and self-oxygenating photodynamic therapy (Scheme 5a,b, c,d). The acid-sensitive MOF encapsulated Ce6 and catalase (CAT), enabling their selective release within the acidic TME. CAT decomposed endogenous H₂O₂ into O₂, alleviating tumor hypoxia and enhancing Ce6-mediated singlet oxygen generation upon laser irradiation, which induced mitochondrial dysfunction, caspase-3-dependent apoptosis, and immunogenic cell death. The resulting exposure of calreticulin (CRT), release of HMGB1 and ATP, and subsequent dendritic-cell maturation and cytotoxic T-cell infiltration further amplified antitumor immunity.Furthermore, EM camouflage improves tumor accumulation, whereas fluorescence and PAI enable real-time image-guided therapy, highlighting the potential of multifunctional MOFs for precision cancer theranostics [137].

Scheme 5.

Schematic illustration of MMCC@EM nanotheranostics for FL/PA duplex imaging- escorted self-oxygenation PDT. (a) The synthetic process of MMCC@EM, (b) The therapeutic mechanism mediated by MMCC@EM., (c) Fluorescence images of 4T1 tumor-bearing mice after i.v. administration of MMCC or MMCC@EM at different time intervals and ex vivo fluorescence images of major organs and tumors at 24 h, (d) 2D/3D-rendered PA/US images ofOxyHb andDeoxyHb of tumor tissues after i.v. administration of MM-Ce6@EMandMMCC@EM at different time points. Adapted from Ref [137]. with permission, (e) Preparation of Z-M-LA@CM. (f) Application of Z-M-LA@CM for visualized “off–on” fluorescence detection of GSH and dual imaging guided CDT/PTT. Adapted from Ref [138], reproduced with permission

In a similar study, Yu et al. developed a homologous cancer cell membrane-coated ZIF-8 nanoplatform that enables glutathione-responsive theranostics through TME activation (Scheme 5e,f). In the glutathione-rich and acidic TME, intracellular GSH degrades MnO₂ to activate nanozyme-mediated chemodynamic therapy and restore fluorescence for tumor-specific imaging. Upon near-infrared irradiation, the nanoplatform simultaneously generates ROS and photothermal effects, resulting in synergistic tumor ablation. Additionally, the biomimetic cell membrane coating enhances tumor targeting, while the combined therapy induces immunogenic cell death and activates antitumor immunity through calreticulin exposure, HMGB1 release, and increased CD4⁺ and CD8⁺ T-cell infiltration. These findings highlight the potential of multifunctional MOF nanoplatforms to integrate tumor-responsive activation, catalytic therapy, multimodal imaging, photothermal therapy, and immune modulation for precision cancer theranostics [138].

He et al. developed a core–shell CuS@MIL-100 MOF nanohybrid that combines NIR-II photothermal therapy with T2-weighted MRI for image-guided cancer treatment (Scheme 6A). The hollow CuS core exhibits efficient photothermal conversion under 1064 nm laser irradiation, generating localized hyperthermia for tumor ablation, while the Fe-based MIL-100 shell provides intrinsic MRI contrast for precise tumor visualization and therapeutic monitoring. Benefiting from the enhanced tissue penetration of the NIR-II window, the nanoplatform achieves effective photothermal therapy with favorable biocompatibility and imaging performance. This study demonstrates the potential of multifunctional MOF nanohybrids to integrate diagnostic imaging and photothermal therapy within a single theranostic platform for precision oncology [139].

Scheme 6.

(A) Schematic diagram depicting the preparation of HCuS @MIL-100 and its application in MRI-guided PTT, infrared thermographic images of tumor-bearing mice under irradiation of 1064-nm laser after being treated with PBS and HCuS@MIL-100,And images of MRI at tumor site in 4T1 tumor-bearing mice before and after intratumoral administration of HCuS@MIL-100. In Ref [139]. reproduced with permission, (B) Schematic Illustration of the MOF-Derived Nanoprobe for Hypoxia Imaging-Guided Tumor Radiosensitization and the Nanoprobe Used for Hypoxia Imaging in Cells and Mice, as described in Ref [140], reproduced with permission

In another example of studies conducted, Chen et al. developed a MOF-derived theranostic nanoprobe (HfC-Hy) that combines hypoxia-responsive molecular imaging with radiotherapy enhancement (Scheme 6B). The nanoplatform consists of Hf-MOF-derived mesoporous carbon NPs containing HfO₂ and fluorophore-labeled single-stranded DNA probes targeting hypoxia-inducible factor-α (HIF-α) mRNA. In hypoxic tumor tissues, specific recognition of HIF-α mRNA restores fluorescence, enabling selective imaging of tumor hypoxia. Simultaneously, the HfO₂ component enhances X-ray energy deposition and radiolytic ROS generation, thereby improving radiotherapy efficacy. Supported by in vivo imaging and therapeutic studies, this work demonstrates a multifunctional MOF-derived strategy that integrates hypoxia detection, fluorescence-guided imaging, and radiosensitization within a single platform for precision cancer therapy [140].

Challenges and limitations

The intrinsic capability of MOFs to integrate diagnostic and therapeutic functionalities within a single platform has positioned them as promising nanotheranostic agents. These multifunctional systems enable synergistic therapeutic approaches that enhance treatment efficacy while overcoming many of the limitations associated with conventional monotherapies [183]. Despite substantial progress in preclinical research, most MOF-based nanotheranostics remain at the experimental stage. While numerous animal studies have demonstrated effective tumor imaging and therapy (e.g., MRI/CT imaging, PTT-mediated tumor ablation), clinical translation remains limited [184]. To date, only a single MOF-based formulation has entered Phase I clinical trials [29, 184]. Several key challenges hinder their clinical advancement, including reproducibility of synthesis, comprehensive safety evaluation, and scalable manufacturing. MOF-related toxicity can arise from multiple factors, such as the type of metal ions used, organic linkers, residual solvents, and particle size distribution. Toxic metals like lead, arsenic, cadmium, and chromium, though occasionally used for specific purposes, are known to cause irreversible cytotoxicity. Therefore, incorporating biocompatible metals such as Zn or Fe is essential to minimize adverse biological interactions.

Moreover, common organic linkers—such as amines, phosphonates, carboxylates, phenolates, and sulfonates—may degrade into potentially harmful byproducts, which complicates their safe application in physiological environments. As highlighted in Nature Reviews, “the dose makes the poison”; hence, careful dose control is crucial to minimize toxicity [184]. Although in vitro and small-animal studies are promising, comprehensive long-term toxicological, pharmacokinetic, and efficacy assessments in larger animal models are still required. Regulatory approval will also depend on standardized characterization of particle size, structural stability, and clearance pathways. Importantly, MOFs offer unique advantages—such as high drug LC% and multifunctionality—which could significantly enhance clinical efficacy. Their ability to improve drug delivery efficiency while reducing systemic toxicity is particularly promising. For imaging, the high contrast per dose offered by MOF-based agents may also lower the required imaging agent dosage. Another major limitation lies in the structural stability of MOFs under physiological conditions, especially within the bloodstream. Inadequate stability may lead to premature degradation and the release of potentially toxic components. A recurring concern is the residual presence of dimethylformamide (DMF), a commonly used solvent in MOF synthesis, which can persist in porous cavities and cause adverse health effects such as hepatotoxicity and gastrointestinal distress. To address this, meticulous optimization of synthetic protocols is essential for eliminating residual solvents and enhancing framework stability under biological conditions [18].

Furthermore, the complex and costly nature of MOF synthesis poses a significant bottleneck for large-scale applications. The dominant solvothermal method, although effective, involves the use of organic solvents and high energy input, which raises concerns regarding environmental and economic sustainability. Therefore, the development of green, scalable, and reproducible synthesis strategies is essential. Several alternative approaches—such as MW, mechanochemical, and aqueous-based methods—are being actively explored to overcome these limitations [185].

With the continuous advancement of biocompatible MOF chemistries and precision-targeting strategies, the coming years may witness the first human trials involving MOF-based theranostic agents, paving the way toward realizing the full potential of these intelligent nanomedicines [184].

Future perspectives

MOFs have emerged as a transformative class of nanomaterials in biomedical science, offering significant potential in drug delivery, multimodal imaging, and disease diagnosis and therapy. Among various nanostructures, MOFs are distinguished by their exceptional structural tunability, high porosity, large surface area, and adjustable size, making them highly adaptable for theranostic applications. These features have propelled research into MOFs beyond conventional boundaries, advancing the field of precision nanomedicine. A breakthrough on the horizon is the integration of artificial intelligence (AI) in MOF design and synthesis. Given the tunable nature of MOFs—through variation of metal nodes, organic linkers, and synthesis conditions—AI-driven computational models can predict optimal synthetic parameters, evaluate structural characteristics, and improve drug-loading and release profiles. Such approaches not only accelerate material discovery but also enhance biocompatibility and therapeutic performance, expediting the translation of MOF-based systems into clinical applications. Another emerging direction is the incorporation of MOFs into wearable biosensors for real-time health monitoring and diagnostics. These devices require materials with long-term stability and high functional surface area—properties inherently present in MOFs. Their modifiable chemistry allows selective recognition of disease biomarkers and controlled modulation of therapeutic responses. The development of MOF-integrated wearable technologies could revolutionize personalized medicine by enabling continuous, on-body health surveillance and precision drug delivery tailored to individual patients.

MOFs also hold great promise in gene therapy, particularly in delivering CRISPR/Cas9 components. Their porous structures and chemical versatility allow for the encapsulation and controlled release of nucleic acid-based cargo, facilitating targeted genetic modification with high specificity and minimal off-target effects. This opens new opportunities in the treatment of hereditary disorders and various cancers, positioning MOFs as next-generation vectors for gene editing technologies. Despite these advancements, key challenges remain. Achieving optimal biocompatibility and biodegradability is critical for clinical translation. The design of MOFs must ensure safe degradation within physiological environments, avoiding accumulation and toxicity. Strategic selection of biocompatible metal ions, non-toxic organic linkers, and environmentally benign solvents is necessary to meet these safety criteria. Current efforts focus on engineering bioresorbable MOFs that maintain functional integrity during treatment while degrading into harmless byproducts post-therapy.

Furthermore, although preclinical results—particularly in small animal models—have been promising, human clinical trials are still in their infancy. Inter-individual variability in physiological responses necessitates extensive pharmacokinetic and toxicological profiling before widespread adoption. Nonetheless, the intrinsic versatility of MOFs enables customization of therapies based on patients’ genetic makeup and disease characteristics, advancing the paradigm of precision and personalized medicine. Beyond oncology, MOFs are gaining attention in the treatment of neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and stroke. Their potential to cross the blood–brain barrier offers a unique advantage for delivering neurotherapeutics directly to affected brain regions. Additionally, their antimicrobial activity makes MOFs attractive for combating multidrug-resistant infections. Some antibiotic molecules can even be incorporated into the MOF structure itself, offering dual functionality as both carrier and therapeutic agent.

In conclusion, MOFs are poised to redefine the future of nanotheranostics. Their integration with AI-driven design, wearable technologies, and advanced genetic therapies underscores their transformative potential in next-generation healthcare. However, addressing the challenges of toxicity, biodegradability, and regulatory compliance remains critical. With sustained interdisciplinary collaboration and innovation, MOFs may evolve into core components of future medical systems—revolutionizing disease diagnosis, treatment, and patient outcomes globally.

Conclusion

MOFs have emerged as a transformative class of porous crystalline materials, offering exceptional advantages in the field of nanotheranostics. Their intrinsic characteristics—including high porosity, large surface area, tunable chemical composition, and structural flexibility—have positioned MOFs at the forefront of biomedical research. The rational design of MOFs allows for precise functionalization, enabling their adaptation to specific diagnostic and therapeutic needs, thereby making them indispensable tools in modern precision medicine. Among their diverse biomedical applications, drug delivery remains one of the most promising. The porous architecture of MOFs facilitates high drug-loading capacities, allowing for the encapsulation of significant quantities of therapeutic agents. These frameworks enable controlled and sustained release, improving pharmacokinetics while minimizing off-target toxicity. Furthermore, the structural tunability of MOFs enhances drug bioavailability and delivery efficiency to diseased tissues, ultimately contributing to improved clinical outcomes and reduced systemic side effects compared to conventional delivery systems.

In addition to drug delivery, MOFs play a crucial role in multimodal imaging, a cornerstone of contemporary diagnostics. Their capacity to integrate with fluorescent molecules, radionuclides, and contrast-enhancing NPs supports real-time, high-resolution imaging of biological processes. This multifunctional behavior enables simultaneous diagnostics and therapy (i.e., theranostics), allowing clinicians to monitor treatment efficacy and dynamically adjust therapeutic regimens. Moreover, MOFs are gaining traction in the field of gene therapy. Their versatile architecture and chemical tunability support the efficient delivery of genetic material, paving the way for targeted, personalized treatments of complex diseases. These advances mark a significant step toward individualized medicine. Nevertheless, challenges remain. Issues related to biocompatibility, long-term toxicity, large-scale synthesis, and cost-effective manufacturing must be systematically addressed to advance clinical translation.

In summary, MOFs represent a paradigm shift in nanotheranostics, bridging the gap between therapy and diagnostics with unprecedented precision and efficiency. Their continued development—through interdisciplinary collaboration across materials science, chemistry, biomedical engineering, and pharmacology—will likely fuel the next generation of biomedical technologies. With sustained innovation and regulatory progress, MOFs are poised to revolutionize the future of nanomedicine, delivering safer, more effective, and patient-centered healthcare solutions worldwide.

Abbreviations

MOF

Metal-Organic Framework

NMOF

Nanoscale metal-Organic Framework

NPs

Nanoparticles

ICG

Indocyanine green

PSM

Post-synthetic modification

DOX

Doxorubicin

5-FU

5-Fluorouracil

MTX

Methotrexate

LC

Loading capacity

EE

Encapsulation efficiency

TCPP

Tetrakis(4-carboxyphenyl) porphyrin

PTT

Photothermal therapy

PDT

Photodynamic therapy

GSH

Glutathione

ALP

Alkaline phosphatase

TME

Tumor Microenvironment

PEG

Polyethylene Glycol

UCNP

Upconversion Nanoparticle

PT

Phototherapy

FL

Fluorescence imaging

OI

Optical imaging

MRI

Magnetic resonance imaging

CT

Computed tomography

PAI

Photoacoustic imaging

PET

Positron Emission Tomography

FA

Folic acid

US

Ultrasound

NIR

Near-infrared

NIRF

Near-infrared fluorescence

GOx

Glucose oxidase

DDSs

Drug delivery systems

EM

Erythrocyte membrane

PSs

Photosensitizers

2-MIM

2-methylimidazole

ROS

Reactive oxygen species

DDP

Cisplatin

PVP

Polyvinylpyrrolidone

RB

Rose Bengal

MW

Microwave-Assisted

Ce6

Chlorin e6

DHA

Dihydroartemisinin

H₂BDC

Terephthalic acid

HA

Hyaluronic acid

BSA

Bovine serum albumin

SCM

Succinimidyl carboxymethyl ester

BTC

1,4-benzene dicarboxylic

CAT

Catalase

PG

Prodigiosin

5-FAM

5-Carboxylfluorescein

Author contributions

Sh. V investigated, M. Z designed, conceptualized, and supervised; Sh. V, F. E, S. M. H performed literature searching and analysis; S. M. R., N. F illustrated figure and tables; Sh. V, M. A., Gh. T., M. Z. wrote the primary draft. I. A. edited and submitted the manuscript. All authors have reviewed and approved the final manuscript.

Funding

This study was supported financially by Iran University of Medical Science, with the grant number 28342.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Clinical trial number

Not applicable.

Generative AI and AI-assisted technologies

During the preparation of the manuscript, ChatGPT is used to develop, enhance and correct the images. After using this tool/service, the author(s) reviewed, edited the content and verified the accuracy and take full responsibility.

Competing interest

The authors declare no competing interests.